As a result of the introduction of hybridoma technology in the late 1970's, monoclonal antibodies, mostly of murine origin, have been made to many types of human cancer. Most of the tumor markers recognized by the xenogeneic monoclonal antibodies are not strictly tumor-specific, but are shared by tumors and certain normal and/or fetal tissues and are therefore referred to as tumor-associated antigens. Whether these tumor-associated antigens, identified by xenogeneic antibodies, are capable of evoking an antitumor response in cancer patients, and whether such antigens are even related to the immune response to autologous tumors in cancer patients, remains to be determined. It is widely felt that tumor growth and dissemination may be due to the lack of an immune response, either because tumor-associated antigens escape recognition or any antitumor responses are suppressed. Thus, antigens which can be made immunogenic might potentially be useful to induce antitumor immunity for therapeutic and possibly prophylactic benefits.
One approach toward manipulating the immune response to such tumor-associated antigens is based on idiotypic interactions. The unique antigenic determinants in and around the antigen combining site (paratope) of an immunoglobulin molecule are known as idiotopes, and the sum of all idiotopes present on the variable portion of a given antibody is referred to as its idiotype. Idiotypes are serologically defined, since injection of a primary antibody which binds an epitope of the antigen of interest may induce the production of anti-idiotypic antibodies.
When the binding between primary antibody and anti-idiotypic antibody is inhibited by the antigen to which the primary antibody is directed, the idiotype is considered to be binding-site related. In essence, the anti-idiotypic antibody recognizes a paratope-associated idiotope of the primary antibody. Since both the anti-idiotypic antibody and antigen bind to primary antibody, the anti-idiotypic antibody and antigen may share a similar three-dimensional conformation which represents the so-called "internal image" of the epitope. There may be reactions between primary antibody and other anti-idiotypic antibodies which are not inhibited by antigen, which may involve idiotopes of primary antibody which are spatially distinct from the paratope binding site, yet are still capable of regulating the immune response.
Anti-idiotypic antibodies which act as internal images of a tumor antigen may be used to prime a de novo response to the tumor antigen. By presenting these images of antigenic epitopes in a different molecular environment, responses may be activated which would otherwise be silent. Nisonoff and Lamoyi, Clin. Immunol. Immunopathol. (1981) 21:397. That is, when the anti-idiotype represents the conformational mirror-image of the antigen, it may substitute for nominal antigen and elicit a primary antibody-like response. Additionally, the anti-idiotypic antibody which mimics antigen may also select or amplify any pre-existing antitumor repertoire by the up regulation of a normally suppressed response. Most naturally-occurring anti-idiotypic populations contain few internal image anti-idiotypes, whereas xenogeneic anti-idiotypic antibodies more frequently succeed as internal image immunogens. Ibid.
Anti-idiotypic antibodies which do not bear the internal image of antigen may also induce antitumor responses by influencing the regulatory idiotypic network. See, Bona, 1984, in Idiotypy in Biology and Medicine, Kohler et al., eds., Academic Press, pp. 29-42. Thus antibodies to framework-associated idiotopes, or regulatory idiotopes, may select or amplify T and/or B cell clones with specificity for tumor antigens. Some evidence, however, suggests that this group of anti-idiotypic antibodies can prime a humoral response but are unable to cause maturation of B cells without further challenge with the nominal antigen (Heyman et al., J. Exp. Med. (1982) 155:994), and thus combination with an internal image anti-idiotypic antibody may be necessary to evoke a desired antitumor response.
Antitumor responses induced by anti-idiotypic manipulation have been shown against both murine (Forstrom et al., Nature (1983) 303:627; Lee et al., Proc. Natl. Acad. Sci. USA (1985) 82:6286) and human (Herlyn et al., Eur. J. Immunol. (1987) 17:1649; Viale et al., J. Immunol. (1987) 139:4250) tumor-associated antigens. Injection of xenogeneic anti-idiotypic antibody has reportedly induced antitumor responses leading to the suppression of tumor growth (Kennedy et al., J. Exp. Med. (1985) 161:1432; Raychaudhuri et al., J. Immunol. (1987) 139:271). However, recent evidence has shown that the presence of certain non-defined epitopes on both anti-idiotypic antibody and T-helper cells are important in the induction of tumor immunity, and different anti-idiotypes may have different effects on tumor growth (Raychaudhuri et al., J. Immunol. (1987) 139:3902).
A glycoprotein antigen of 72 kilodalton molecular weight (gp72) has been associated with colorectal, ovarian carcinomas, osteogenic sarcomas, and other malignancies (Price et al., Brit. J. Cancer (1984) 49:809; Campbell et al., Int. J. Cancer (1984) 34:31; Powell et al., Amer. J. Obstet. Gynecol. (1987) 157:28), as originally identified in the 791T sarcoma cell line. Murine monoclonal antibody 791T/36 reacts with a determinant of the gp72 antigen. Embleton et al., Br. J. Cancer (1981) 43:582. This monoclonal antibody has been coupled to imaging agents for use in the immunoscintigraphy of tumors, and has been coupled to cytotoxins such as ricin A chain, daunomycin and methotrexate and used as a targeting molecule. Patients receiving monoclonal antibody 791T/36 or ricin A chain-791T/36 immunoconjugates have been shown to develop anti-idiotypic antibodies. Rowe et al., IRCS Medical Science (1985) 13:936; Pimm et al., J. Nucl. Med. (1985) 26:1011; and Robins et al., J. Immunol. Meths. (1986) 90:165.
The use of anti-idiotypic antibodies to manipulate immune responses is a potentially new approach to cancer therapy. However, the vast majority of anti-idiotype polyclonal and monoclonal antibodies have been produced in animals other than man. These antibodies possess major disadvantages for treatment of tumors in humans. The continuous exposure of heterologous immunoglobulin molecules which may be required to induce an antitumor response may lead to the production of anti-isotypic antibodies and the rapid elimination of the anti-idiotype.
One possible way to overcome these difficulties is through the administration of human anti-idiotypic antibodies, preferably monoclonal. It is not at all clear, however, that the human tumor-associated antigens uncovered with xenogeneic antibodies are capable of evoking an antitumor response in humans. Moreover, the existence of human antibodies which are internal images of particular antigenic epitopes of the gp72 molecule is unknown. The surprising discovery of the human anti-idiotypic monoclonal antibodies of the present invention overcomes several of these problems and fulfills other related needs.